3-Cyano-2-pyridinyloxymethyl-oxazolidine derivatives

ABSTRACT

Novel 2-(3-tert. butyl or isopropylamino-2-hydroxypropoxy)-3-cyanopyridines, their pharmaceutically acceptable salts and their preparation are disclosed. These pyridines are vasodilators having anti-hypertensive activity of rapid onset and extended duration and reduced tendency to cause undesirable tachychardia; they are also β-adrenergic blocking agents.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 713,558, filed Aug. 11, 1976which in turn is a continuation-in-part of application Ser. No. 533,385,filed Dec. 16, 1974, now U.S. Pat. No. 4,000,282 issued Dec. 28, 1976.

BACKGROUND OF THE INVENTION

The present invention concerns 2-substitutedaminohydroxypropoxy-3-cyanopyridines which have antihypertensiveactivity of rapid onset and extended duration and are β-adrenergicblocking agents.

Hypertension in man and other animals can be treated with variouschemical agents. One such class of agents is that known as theβ-adrenergic blocking agents or β-blockers. While this class of agentscan have antihypertensive activity, the onset of this activity isgenerally gradual. The structure and activity of β-blockers is generallydiscussed in "Clinical Pharmacology and Therapeutics" 10, 252,306(1969). Cyano substituted carbocyclic and heterocyclic aryl β-adrenergicblocking agents are disclosed in Belgian patent 707,050 and Netherlandspatent 69.07700. Cyano substituted heteroaryl β-adrenergic blockingagents are also disclosed in German Pat. No. 2,406,930.

Another class of anti-hypertensive agents are the vasodilators.Vasodilators, however, normally cause undesirable tachychardia.

Novel 2-(3-C₃ -C₄ -branchedalkylamino-2-hydroxypropyxy)-3-cyanopyridines have been discovered.These compounds are vasodilators having antihypertensive activity ofrapid onset and extended duration and a reduced tendency to causeundesirable tachychardia - and they are β-adrenergic blocking agents.

SUMMARY OF THE INVENTION

Novel 2-(3-tert. butyl orisopropylamino-2-hydroxypropoxy)-3-cyanopyridines and theirpharmaceutically acceptable salts which are vasodilators having rapidand lasting antihypertensive effect and a reduced tendency to causetachchardia and are also β-adrenergic blocking agents.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

An embodiment of the present invention is compounds having the formula##STR1## wherein R is isopropyl or tert. butyl, and pharmaceuticallyacceptable salts thereof. A preferred substituted pyridine is 2-(3-tert.butyl-2-hydroxypropoxy)-3-cyanopyriline and its pharmaceuticallyacceptable salts.

The substituted pyridines of the present invention include all theoptical isomer forms, that is mixtures of enantiomers e.g. racemates aswell as the individual enantiomers. These individual enantiomers arecommonly designated according to the optical rotation they effect, by(+) and (-), (L) and (D), (1) and (d) or combinations of these symbols.The symbols and (R) stand for sinister and rectus respectively anddesignate an absolute spatial configuration of the enantiomer.

The pyridines of the present invention can be prepared by any convenientprocess.

One such process involves the coupling of a 2-halo-3-cyanopyridine witha suitable substituted oxazolidine and hydrolysing the reaction productobtained. This process is illustrated by the following set of reactionequations: ##STR2## R in the above equations is tert. butyl orisopropyl. M is an alkali metal, either potassium or sodium. R₁ can behydrogen or the residue of any suitable aldehyde e.g. arylaldehyde, suchas benzaldehyde, napthaldehyde and the like, or alkanal such asacetaldehyde, butyraldehyde and the like. The process for preparingoxazolidines where M is hydrogen is disclosed in U.S. Pat. No. 3,718,647and U.S. Pat. No. 3,657,237 and to the extent necessary the pertinentdisclosure is incorporated herein by reference. The alkali metal salt ofthe oxazolidine is prepared in a conventional manner by reaction of thecorresponding hydroxymethyl oxazolidine with an appropriate amount ofbase such as potassium hydroxide, sodium hydroxide, sodium methoxide andthe like. However, this Reaction A may also be carried out with in-situformation of the alkali metal oxazolidine salt of Formula IV by reactingthe oxazolidine ##STR3## with the Formula II pyridine in the presence ofa strong base such as an alkali metal alkoxide (e.g. K--O--C--(CH₃)₃) orhydroxide (e.g. NaOH) or sodium hydride.

The coupling reaction can be carried out at temperatures ranging fromabout 0° to about 100° C. A temperature range of about 10° to about 50°C is preferred. The reaction is generally carried out in a solvent. Anysuitable solvent may be used. Examples of useful solvents aredimethylformamide, dimethylsulfoxide hexamethylphosphoramide, C₁ -C₆alkanols and the like. The hydrolysis is carried out using conventionalacid hydrolysis reagents and techniques e.g. treatment with a solutionof any strong mineral acid such as HCl or H₂ SO₄.

The coupling reaction is ordinarily carried out at atmospheric pressure.Higher pressures may be used if desired.

When the racemic oxazolidine (Formula III or V) is used as a reactant,the Formula I product is obtained as a racemate. The racemate may beseparated into its individual enantiomers by conventional resolutiontechniques.

When R₁ in the oxazolidine (e.g. Formulae III, IV or V) is other thanhydrogen, in addition to the chiral center at oxazolidine position 5there is a second chiral center at position 2. However, whenever theoxazolidine is designated as (S), (R) or (R,S), this designation refersonly to the optical configuration around the carbon atom at the 5position.

By using a single optical isomer of the Formula IV or V oxazolidine inthe above reactions, the Formula I product may be obtained directly as asingle enantiomer. Thus, if the S-isomer of the oxazolidine is used,then the product obtained will be the S-isomer. This provides aconvenient way for directly preparing individual isomers of the presentpyridines.

The compounds of the present invention also include the pharmaceuticallyacceptable salts of the novel pyridines. These salts are generally saltsof the Formula I pyridines and organic or inorganic acids. These saltsare prepared by treating the pyridine with an appropriate amount of auseful acid, generally in a suitable solvent. Examples of useful organicacids are carboxylic acids such as maleic acid, acetic acid, tartaricacid, propionic acid, fumaric acid, isethionic acid, succinic acid,pamoic acid, oxalic acid and the like; useful inorganic acids arehydrohalo acids such as HCl, HBr, HI; sulfuric acid, phosphoric acid andthe like.

The compounds of the present invention have a dual action. They are (1)vasodilators having antihypertensive activity of rapid onset andextended duration and reduced tendency to cause undesirable tachychardiaand (2) β-adrenergic blocking agents. This antihypertensive activity isbelieved to be the result of peripheral vasodilation via a mechanism notdirectly related to β-adrenergic blockade. Thus, the present pyridinesprovide (a) an advantage over ordinary vasodilators since vasodilatortreatment normally results in an undesirable tachychardia response and(b) an advantage over the ordinary β-adrenergic blocking agent by havingan immediate and substantial antihypertensive effect.

This rapid onset antihypertensive activity is determined byadministering (orally) a representative pyridine of Formula I tospontaneously hypertensive (SH) rats and measuring the effect on bloodpressure. A representative substituted pyridine, (S)-2-(3-tert.butylamino-2-hydroxypropoxy)-3-cyanopyridine hydrochloride, was found torapidly lower the SH rat's blood pressure.

The β-adrenergic blocking activity of the present pyridines isdetermined by measuring the ability of a representative pyridine toblock isoproterenol induced β-adrenergic stimulant effects such as heartrate increase, hypotension and bronchodilatation, in animals. Arepresentative pyridine,(S)-2-(3-tert.-butylamino-2-hydroxypropoxy)-cyanopyridine hydrochloride,was administered intravenously and found to behave as a β-adrenergicblocking agent by this protocol.

The ability of the present pyridine to reduce blood pressure, in an SHrat, rapidly and for extended duration, indicates that the presentpyridines and their salts are useful to treat hypertension in humans.Likewise, the observed β-adrenergic blocking activity of these pyridinesindicates that they are useful in humans as β-adrenergic blockingagents.

For use as antihypertensives and/or β-adrenergic blocking agents, thecompounds of the present invention can be administered orally, byinhalation, by suppository or parenterally i.e. intravenously,intraperitoneally, etc. and in any suitable dosage form. The compoundsmay be offered in a form (1) for oral administration e.g. as tablets incombination with other compounding ingredients (diluents or carriers)customarily used such as talc, vegetable oils, polyols, benzyl alcohols,starches, gelatin and the like - or dissolved, dispersed or emulsifiedin a suitable liquid carrier - or in capsules or encapsulated in asuitable encapsulating material; or (2) for parenteral administration,dissolved, dispersed, or emulsified in a suitable liquid carrier ordiluent or (3) as an aerosol or (4) as a suppository. The ratio ofactive ingredient (present compound) to compounding ingredients willvary as the dosage form requires.

The dosage level for the present compounds may be varied from about 0.01mg. to about 50 mg. per kilogram of animal body weight per day. Dailydoses ranging from about 0.04 to about 2.5 mg/kg are preferred, withabout 0.08 to about 1.25 mg/kg being a more preferred range. Oraladministration is preferred. Either single or multiple daily doses maybe administered depending on unit dosage.

Following are examples illustrating pharmaceutical formulationscontaining the pyridines of the present invention. Conventionalprocedures are used for preparing these formulations.

    ______________________________________                                        TABLET FORMULATION                                                            INGREDIENT              AMOUNT (Mg.)                                          ______________________________________                                        2-(3-isopropylamino-2-hydroxypropoxy)-                                                                5.0                                                   3-cyanopyridine hydrogen maleate                                              calcium phosphate       120.0                                                 lactose                 50.0                                                  starch                  23.5                                                  magnesium stearate      1.5                                                   CAPSULE FORMULATION                                                           INGREDIENT              AMOUNT (Mg.)                                          ______________________________________                                        (R)-2-(3-t-butylamino-2-hydroxypropoxy                                                                5                                                     3-cyanopyridine                                                               magnesium stearate      2.0                                                   lactose, U.S.P.         19.3                                                  INJECTABLE SOLUTION                                                           INGREDIENT              AMOUNT (Mg.)                                          ______________________________________                                        2-(3-t-butylamino-2-hydroxypropoxy)-                                                                  1                                                     3-cyanopyridine                                                               sodium chloride         9                                                     distilled water, q.s. 1.0 ml.                                                 LIQUID SUSPENSION                                                             INGREDIENT              AMOUNT (g/l)                                          ______________________________________                                        (S)-2-(3-isopropylamino-2-hydroxypro-                                                                 5.0                                                   poxy)-3-cyanopyridine hydrochloride                                           Veegum H.V.             3.0                                                   methyl paraben          1.0                                                   kaolin                  10.0                                                  glycerin                250.0                                                 water, q.s. → 1 liter                                                  ______________________________________                                    

The following examples illustrate preparation of a representativepyridine of Formula I. All parts and percentages are by weight unlessotherwise indicated.

EXAMPLE 1 (S)-2-(3-tert. butylamino-2-hydroxypropoxy)-3-cyanopyridinehydrochloride

To (S)-2-phenyl-3-tert. butyl-5-hydroxymethyloxazolidine (7 grams, 0.03moles) in 35 ml. of N,N-dimethylformamide (DMF) is added 1.3 grams (0.03moles of sodium hydride (57% dispersion in mineral oil). This mixture isheated 5 minutes over steam and then is allowed to stir 15 minutes atroom temperature. 4.1 grams (0.03 moles) of 2-chloro-3-cyanopyridine in20 ml of DMF is then added and the resultant reaction mixture is stirredfour hours at room temperature. Water is then added and an oilseparates. This oil is extracted three times with 25 ml of chloroformeach time. This chloroform extract is dried over sodium sulfate andconcentrated under reduced pressure (20 mm) over steam to yield theproduct, (S)-2-phenyl-3-tert.butyl-5-(3-cyano-2-pyridyloxymethyl)oxazolidine, as an oil. This oil isthen suspended in 1N HCl (50 ml), heated 5 minutes over steam and thenis stirred for 15 minutes at room temperature. The solution obtained isthen extracted twice with 25 ml of diethylether each time. The extractedaqueous layer is made basic by addition of saturated aqueous sodiumcarbonate solution. This aqueous solution is then extracted with ethylacetate (3 × 25 ml) and the ethylacetate solution is dried over sodiumsulfate. The dried ethyl acetate solution is then concentrated underreduced pressure (20 mm) over steam to yield an oil. This oil ischromatographed on alumina. The chromatographic fractions areconcentrated to yield an oil which is dissolved in diethyl ether.Ethanolic HCl (saturated solution) is added to this ether solution untilsolid separation is substantially complete. The separated semi-solid isrecrystallized from isopropanol/ether (ether added to isopropanol to thepoint of turbidity) to yield 1 gram of(S)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-cyanopyridinehydrochloride, melting at 161°-163° C.

While in Example 1 the S-isomer of the pyridine salt is prepared, theracemate is prepared by using racemic (S/R) oxazolidine reactant; theR-isomer is prepared by using R-oxazolidine reactant.

The free amine is obtained from the Example 1 salt by any conventionalprocedure e.g. by treating the salt with a base (e.g. NaOH) in solutionand extracting the free amine therefrom.

Using the procedure of Example 1,(S)-2-(3-isopropylamino-2-hydroxypropoxy)-3-cyanopyridine hydrochlorideis prepared by using the corresponding N-isopropyl oxazolidine in placeof the N-tert. butyl oxazolidine.

Claims to the invention follow.

What is claimed is:
 1. A compound having the formula ##STR4## wherein Ris tert. butyl or isopropyl and R₁ is hydrogen.
 2. Compound of claim 1having the S-isomer configuration.
 3. Compound of claim 1 having theR-isomer configuration.
 4. Compound of claim 1 wherein R is isopropyl.5. Compound of claim 1 wherein R is tert. butyl.
 6. Compound of claim 5having the S-isomer configuration.